tbuckley/cabot-search huggingface dataset:
Abstract 424: Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy
Authors: Junhai Xu, Jimin Xu, Ruixia Ma, Mingxiang Zhou, Doerte R. Fricke, Haiying Chen, Hyejin Kim, Xi Liu, Jia Zhou, Qiang Shen
Journal: Cancer Research (2022)

Abstract Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, is constitutively activated in various human cancers, and has been recognized as an attractive therapeutic target in cancer. STAT3 protein dimerizes and translocates to the nucleus to eventually transactivate downstream target genes. Despite some progress has been made in the past two decades, to date there is still lack of FDA-approved STAT3 inhibitors available for clinical use. Recently, proteolysis-targeting chimera (PROTAC) technology has dramatically advanced the development of therapeutics by introducing targeted protein degradation. Previously, our team has developed HJC0152, a promising STAT3 inhibitor, via structure- and fragment-based drug design strategies and in silico molecular modeling and docking. HJC0152 has demonstrated an attractive cancer therapeutic and preventive efficacy by targeting the non- estrogen receptor (ER)-based STAT3 signaling pathway. To achieve better potency and inhibition of STAT3 signaling, we therefore developed a series of HJC0152-based PROTAC protein degraders. These potential anticancer agents have been initially evaluated and several showed favorable potency in inhibiting the proliferation in a panel of breast cancer cell lines. We found that compounds JMX1122, JMX1123, and JMX1124 significantly inhibited proliferation and colony formation of a highly aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and the ER-positive breast cancer cell lines. Different from the lead compound HJC0152, which showed an early inhibition on the phosphorylation of STAT3 at the Tyr705 and Ser727 residues, the newly developed HJC0152-PROTACs showed a significantly late differential inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues, and reduced the total STAT3 protein level at 72 hours of treatment. Our current results support the notion that HJC0152-based PROTAC degraders potently suppress breast cancer cell proliferation and induce apoptosis, via direct targeting of STAT3 and its protein degradation. These compounds are currently being investigated for breast cancer cell migration and invasion, and will be evaluated for the in vivo inhibition of tumor growth and metastasis in different mouse models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z. Citation Format: Junhai Xu, Jimin Xu, Ruixia Ma, Mingxiang Zhou, Doerte R. Fricke, Haiying Chen, Hyejin Kim, Xi Liu, Jia Zhou, Qiang Shen. Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 424.
Abstract 1621: Comparison and consequences of different implantation techniques on the orthotopic growth of syngeneic Hepa1-6 liver cancer cells
Authors: Cynthia Obodozie, Sandra Moor, Gojko Bijelic, Muriel Malaisé, Philipp Metzger, Holger Weber
Journal: Cancer Research (2022)

Abstract Checkpoint inhibitor treatment has become a common therapy of various cancer types. Still, there is a need for well-characterized preclinical mouse models, as clinical data indicates that patients only partially respond to immune modulatory regiments. When compared to the classical subcutaneous or subQperior࣪ (implantation into the mammary fat pad) syngeneic mouse models, orthotopic models are considered more predictive, since implantation of tumor cells into the organ of origin allows organotypical interaction between tumor cells and the surrounding stroma, including immune cells. Up until now, our standard procedure for an orthotopic Hepa1-6 liver model is the injection of Hepa1-6 cells into the spleen with the subsequent migration of the injected Hepa1 6 cells into the liver for five minutes via Vena lienalis. A major drawback of this method for a syngeneic model in immune-competent mice is the following resection of the spleen, a prominent secondary lymphoid organ. Therefore, we tested two other implantation methods: the direct injection of Hepa1-6 cells into a liver lobe using Matrigel࣪ and the injection of Hepa1-6 cells into the portal vein. In contrast to the standard procedure, both new test methods have in common an excessive bleeding potential which must be prevented. As the Hepa1-6 cells are transduced with luciferase, their growth can be monitored in vivo by bioluminescence imaging and the growth characteristics will be compared. In addition to the growth, the composition of the immune populations will be analyzed staining with the all-in-one flow cytometry panel which permits the differentiation of the main immune cell populations in the tumor, such as T cells (CD4+, CD8+, Treg), B and NK cells, macrophages (M1/M2), MDSCs (granulocytic and monocytic), and dendritic cells. The data will help to select the most suitable method for testing new drug candidates in an orthotopic liver tumor environment. Citation Format: Cynthia Obodozie, Sandra Moor, Gojko Bijelic, Muriel Malaisé, Philipp Metzger, Holger Weber. Comparison and consequences of different implantation techniques on the orthotopic growth of syngeneic Hepa1-6 liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1621.
Abstract 1559: Repurposing of pimavanserin tartrate for the treatment of glioblastoma
Authors: Carson Zabel, Sharavan Ramachandran, Sanjay Srivastava
Journal: Cancer Research (2022)

Abstract Glioblastoma is a highly aggressive brain tumor that has a median survival of 15 months. We aim to give a substitute to the current chemotherapeutic drug temozolomide by using the FDA-approved anti-psychotic pimavanserin tartrate (PVT). To uncover the effectiveness of PVT, we did cytotoxicity assays using SRB to determine the percentage of cell survival in a dose-dependent and time-dependent manner. The apoptotic effects were measured using Annexin-V/APC assay. The mechanism of action was determined utilizing Western Blotting. In different glioblastoma tumor cell lines, the IC50 for 24 hours was between 6 µM and 10 µM. 48 and 72 hours had an IC50 between 4 µM and 6 µM. SF188 glioblastoma cell line had approximately 70% to 80% more apoptotic cells in 10 µM PVT when compared to control in Annexin-V/APC assay. PVT causes a strong modulation of the PI3K/AKT and MAPK pathways when given in increasing concentration at 48 hours. The level of apoptosis was confirmed through Western Blot as well using apoptotic markers. The preliminary data show the ability of PVT to cause apoptosis of glioblastoma tumor cells in vitro through the AKT and MAPK signaling. Citation Format: Carson Zabel, Sharavan Ramachandran, Sanjay Srivastava. Repurposing of pimavanserin tartrate for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1559.
Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy
Authors: Rachel Thijssen, Luyi Tian, Mary Ann Anderson, Christoffer Flensburg, Andrew Jarratt, Alexandra L. Garnham, Jafar S. Jabbari, Hongke Peng, Thomas E. Lew, Charis E. Teh, Quentin Gouil, Angela Georgiou, Tania Tan, Tirta M. Djajawi, Constantine S. Tam, John F. Seymour, Piers Blombery, Daniel H. D. Gray, Ian J. Majewski, Matthew E. Ritchie, Andrew W. Roberts, David C. S. Huang
Journal: Blood (2022)

Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.
Abstract 3026: Inhibition of glutaminolysis overcomes metabolic adaptation to devimistat treatment
Authors: Liwei Lang, Fang Wang, Chloe Shay, Yonggang Ke, Nabil Saba, Yong Teng
Journal: Cancer Research (2022)

Abstract The identification and development of reagents that can limit preferential metabolic effectors in tumors as well as trigger unfavorable tumoral metabolic cues is of tremendous importance for suppressing malignancy. However, insufficient blocking of critical metabolic dependencies of cancer allows the development of metabolic bypasses, which significantly dampens therapeutic benefits of selective agents that target a single metabolic enzyme or pathway. We report here that head and neck squamous cell carcinoma (HNSCC) cells display strong addiction to glutamine. Devimistat, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, devimistatinhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to devimistat treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. These novel and significant findings could lay a scientific foundation for developing more effective treatments targeting the metabolic requirements of HNSCC. Citation Format: Liwei Lang, Fang Wang, Chloe Shay, Yonggang Ke, Nabil Saba, Yong Teng. Inhibition of glutaminolysis overcomes metabolic adaptation to devimistat treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3026.
Abstract 3997: Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer
Authors: Arpit Dheeraj, Dhanir Tailor, Angel Resendez, Fernando Jose Marques, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra
Journal: Cancer Research (2022)

Abstract Aberration in the protein translation can lead to changes in the protein expression that can serve as the drivers of tumor progression. Ribosomes are a molecular machine that acts as a hub for protein synthesis, and dysregulation of ribosome function is causative for cancer formation. Our investigation on the causes of breast cancer progression has identified a small molecule ‘SU056’ that shows efficacy against TNBC models. SU056 treatment inhibits growth and clonogenic potential of TNBC cells (MDA-MB-231, MDA-MB-468, SUM159, 4T1, EMT6 and E0771), by arresting the cell cycle progression through G2/M phase. Proteomics analysis suggested translational process as a target of SU056 in these cells. We found that its treatment modulated expression of several molecules of translational complex such as RPL (RPL9, RPL11, RPL15), RPS (RPSA, RPS9, RPS16, RPS20), and translation initiation factors (eIF6, eIF5, eIF4A, eIF4G), which leads to overall inhibition. This was further confirmed by tumor xenograft study with different TNBC models, which also showed that metastatic nodules in the lungs were inhibited by SU056 compared to control group. The results were further confirmed in a Patient Derived Xenograft (PDX) model SUTI151. Overall, our study has identified a lead candidate SU056, and provides strong foundation to further develop a new therapy for treatment of patients with TNBCs. Citation Format: Arpit Dheeraj, Dhanir Tailor, Angel Resendez, Fernando Jose Marques, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra. Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3997.
Abstract 2683: Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death
Authors: Jassy Mary Lazarte, Nada Tawfeeq, Yonghao Jin, Nazarius Lamango
Journal: Cancer Research (2022)

Abstract Female breast cancer has now surpassed lung cancer as the most common cancer overall in both sexes with an estimated 2.3 million new cases, representing 11.7% of all cancer cases worldwide in 2020. Triple negative breast cancer (TNBC) has been the subject of intensive studies due to its aggressive nature which makes it difficult to treat. Since inclusive treatment for this type had been elusive for decades, it is thus imperative to develop new therapeutic agents to mitigate its deadly effects. PCAIs are novel compounds designed to mimic the essential posttranslational modifications of G-proteins such as KRAS. This study elucidates the effect of the PCAIs downstream of KRAS, specifically on the mitogen activated pathway kinase (MAPK) enzymes. Two breast cancer cell lines, MDA-MB-468 and MDA-MB-231, were used to determine the levels of phosphorylation in several MAPK pathway enzymes. After exposure of the cells to varying concentrations of PCAIs (NSL-YHJ-2-27) for 48 hours, western blot results showed remarkable differences in the phosphorylated levels of the respective enzymes in cells treated with 5 µm of the PCAIs as compared to the control (NSL-YHJ-2-62). Interestingly, the cell lines reacted differently after treatment, in which MDA-MB-468 cells showed increased levels of phosphorylated MEK, ERK, and 90RSK by 122, 273 and 242%, respectively. However, in MDA-MB-231, only the phosphorylated 90RSK showed an increase of 105% and no changes in the other two enzymes. Moreover, a very distinct difference was observed in the levels of phosphorylated BRAF (p-BRAF) and CRAF (p-CRAF). In MDA-MB-231 cells, no change in p-BRAF levels while a 184% increase in p-CRAF were observed. In MDA-MB-468, p-BRAF increased by 41% and p-CRAF decreased by 58%. The differences in the response of the cell lines may reflect their unique genetics. These results show the ability of the PCAIs to interfere with the MAPK pathway. As this signaling cascade plays a very important role in cell response as well as in the progression of cancers, therefore, therapeutics targeting this pathway have a great potential in the development of treatments not only for TNBC but also for other kinds of cancers. Citation Format: Jassy Mary Lazarte, Nada Tawfeeq, Yonghao Jin, Nazarius Lamango. Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2683.
Abstract PL02-01: The pathogenesis of cancer susceptibility due to inherited DNA repair defects
Authors: Michael R. Stratton
Journal: Cancer Research (2022)

Abstract The landscapes of somatic mutation in the genomes of normal human cells have, until recently, been poorly described compared with those of cancer cells. However, advances in technology are now changing this picture and are enabling exploration of the earliest stages of cancer development. In this talk, the patterns of somatic mutation found in normal colorectal epithelial cells are outlined and serve as a backdrop to understanding the pathogenesis of colorectal cancer susceptibility syndromes. Multiple mutational signatures are present in normal colorectal epithelial cells indicating that multiple mutational processes are operative in them during the course of life. Some of these mutational signatures are ubiquitous, present in every colorectal epithelial cell, with mutations generated at constant rates throughout life. Others are sporadic, found only in some cells or in some people, with mutations generated in bursts. Some are of endogenous origins whereas others are caused by exogenous exposures. Several inherited colorectal cancer predisposition syndromes are known to be mediated by DNA repair deficiencies that ultimately generate elevated somatic mutation rates. The results presented here show that in some of these syndromes all normal colorectal cells, and probably all cells in the body, have markedly elevated somatic mutation rates throughout life with mutational signatures not found in healthy individuals. Conversely, in other syndromes normal cells have normal mutation rates with standard mutational signatures but a small minority of cells acquire elevated mutation rates during the course of life. In both scenarios only a small proportion of cells with elevated mutation rates ever become adenomas or carcinomas. The results elucidate the different ways in which elevated somatic mutation rates due to DNA repair deficiencies lead to cancer and potentially offer a new modality contributing to clinical management of colorectal cancer susceptibility. They also provide a new perspective on the role of somatic mutations in ageing. Citation Format: Michael R. Stratton. The pathogenesis of cancer susceptibility due to inherited DNA repair defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL02-01.
Abstract 3459: Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels
Authors: Gevick Safarians, Itay Solomon, Alireza Sohrabi, Stephanie Seidlits
Journal: Cancer Research (2022)

Abstract Hyaluronic acid (HA) is a highly abundant glycosaminoglycan within the central nervous system. In glioblastoma (GBM), interactions with HA mediate tumor cell invasion. An improved knowledge of the biological underpinnings of HA-dependent GBM cell migration can facilitate the development of efficacious therapeutics. To better study how HA in the tumor matrix affects invasion, we have developed a tunable, 3D culture system in which to study gliomaspheres (GSs) of patient-derived tumor cells. Photopolymerization (365 nm for 15 seconds) of GSs suspended in a solution 0.025 w/v% lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), thiolated 4-arm poly-ethylene glycol (20 kDa, Laysan Bio), 8-arm poly-ethylene glycol-norbornene (20 kDa, Laysan Bio), thiolated peptides containing an ‘RGD’ amino acid motif, and either 0.10, 0.25, 0.50, or 0.75 w/v% of thiolated HA (700 kDa average molecular weight, Lifecore Biomedical) yielded 3D hydrogels of varying HA concentrations and similar mechanical properties. Relative invasive capacity, quantified by shape factor (deviation from circularity) and migration length (maximum extension length of processes from the GS periphery), differed across patient lines and was independent of their Cancer Genome Atlas (TCGA) classification as either mesenchymal or proneural. Hydrogels with higher amounts of HA (&amp;gt;0.25% w/v) generally enhanced invasion as compared to low HA (0.10 w/v%) hydrogels. In certain cell lines, a biphasic relationship between HA concentration and migration was observed, in line with previous reports of CD44 expression and migration. Moreover, inhibition of the CD44-Ezrin-Actin axis, using NSC668394, reduced migratory activity in hydrogels with higher HA (&amp;gt;0.25% w/v), while slightly increasing invasion in hydrogels with low HA (0.10 w/v%). In sum, results demonstrate the use of a matrix-mimetic, 3D hydrogel system in which to study GBM invasion through the local extracellular matrix. Citation Format: Gevick Safarians, Itay Solomon, Alireza Sohrabi, Stephanie Seidlits. Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3459.